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Introduction Treatment with alemtuzumab is highly effective in relapsing–remitting multiple sclerosis; however, 30% of patients develop autoimmunity. Alemtuzumab (previously called Campath 1-H) induces a prolonged T-cell lymphopenia with memory cells dominating the reconstituting T-cell pool for at least 3 months. Results Here we show that B-cell recovery is rapid, returning to baseline by 3 months and rising to 165% of baseline by 12 months after treatment. Immature transitional 1 B cells are the predominant cell type 1 month after treatment. This coincides with a surge in serum B-cell activating factor (BAFF), which remains elevated by 33% for at least 12 months after alemtuzumab. BAFF is critical for transition to the mature naive B-cell phenotype, which dominates from 3 months after alemtuzumab. Differentiation to memory B cells is slow so there are radical and prolonged alterations to the B-cell pool after alemtuzumab.

SARS-CoV-2 infection represents a global health problem that has affected millions of people. The fine host immune response and its association with the disease course have not yet been fully elucidated. Consequently, we analyze circulating B cell subsets and their possible relationship with COVID-19 features and severity. Using a multiparametric flow cytometric approach, we determined B cell subsets frequencies from 52 COVID-19 patients, grouped them by hierarchical cluster analysis, and correlated their values with clinical data. The frequency of CD19 B cells is increased in severe COVID-19 compared to mild cases. Specific subset frequencies such as transitional B cell subsets increase in mild/moderate cases but decrease with the severity of the disease. Memory B compartment decreased in severe and critical cases, and antibody-secreting cells are increased according to the severity of the disease. Other non-typical subsets such as double-negative B cells also showed significant changes according to disease severity. Globally, these differences allow us to identify severity-associated patient clusters with specific altered subsets. Finally, respiratory parameters, biomarkers of inflammation, and clinical scores exhibited correlations with some of these subpopulations. The severity of COVID-19 is accompanied by changes in the B cell subpopulations, either immature or terminally differentiated. Furthermore, the existing relationship of B cell subset frequencies with clinical and laboratory parameters suggest that these lymphocytes could serve as potential biomarkers and even active participants in the adaptive antiviral response mounted against SARS-CoV-2.

Transitional B cells (TrB cells) represent a crucial link between immature B cells in the bone marrow and mature peripheral B cells. Although TrB cells represent one of the regulatory B cell subpopulations in healthy individuals, the frequency of CD24 hi CD38 hi TrB cells in circulation may be altered in individuals with autoimmune diseases, such as multiple sclerosis, neuromyelitisoptica spectrum disorders, systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, systemic sclerosis, and juvenile dermatomyositis. Although TrB cells play regulatory roles under inflammatory conditions, consequences of their functional impairment vary across autoimmune diseases. Since the origin, development, and function of TrB cells, especially in humans, remain unclear and controversial, this review aimed to discuss the characteristics of TrB cells at steady state and explore their role in various immune diseases, including autoimmune rheumatic diseases and neuroimmunological diseases.

Background Early initiation of effective treatment is associated with positive long-term prognosis for patients with rheumatoid arthritis (RA). Currently, there are no biomarkers in clinical use to predict treatment response. A predictor of treatment response may be the B-cell compartment, as this is altered in RA patients, making it a potential candidate for predicting treatment response. In this study, we sought to identify B-cell subset(s) at diagnosis that might be associated with Clinical Disease Activity Index (CDAI) remission at 24-week follow-up. Methods Seventy early RA patients from the NORD-STAR trial, recruited from two Swedish sites, and 28 matched healthy controls, were included in this spin-off study. In NORD-STAR, all patients were randomized to methotrexate (MTX) combined with 1) prednisolone, 2) anti-TNF (certolizumab-pegol), 3) CTLA4-Ig (abatacept), or 4) anti-IL-6R (tocilizumab). Circulating B-cell subsets at diagnosis were assessed by flow cytometry. The primary outcome measure was remission according to CDAI <= 2.8. A multivariate two-part discriminant analysis was performed to assess whether B-cell subpopulations at diagnosis could predict remission at 24 weeks. Subsequent univariable statistical analyses were performed using t-tests, Mann-Whitney U, or Kruskal-Wallis tests, as appropriate. Correlations were analyzed using Spearman or Pearson tests, depending on data type. The impact of specific B-cell populations on remission at week 24 was assessed using logistic regression models. The logistic regression model was also used to simultaneously visualize the sensitivity and specificity of the model for all possible values of the exposure (B-cell subpopulations) in predicting the outcome. Results Patients who achieved CDAI remission at 24 weeks had higher proportions of transitional (p < 0.01) and CD21(-) PD-1(+) (p < 0.01) B cells at diagnosis compared to those who did not. When the two B-cell populations were combined, the sensitivity and specificity for remission, including all treatment arms, were 59% and 86%, respectively. Stratification of the patients by treatment arm revealed a significant negative correlation between the proportion of transitional B cells at baseline and disease activity after 24 weeks of treatment with either MTX and prednisolone or anti-IL-6R. Conclusions Our results indicate that transitional and CD21(-) PD-1(+) B cells are associated with remission in early RA. Clinical trial number Not applicable.

Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells.

While durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive LLPC may improve the treatment of antibody-driven autoimmune diseases. However, LLPC remain a challenging therapeutic target. Here, we compare the matched bone marrow (BM) and peripheral blood (PBL) plasma cell (PC) compartments of SLE and healthy donors (HD). We show a similar distribution of CD138- and CD138+ PC, including putative LLPC (CD19- CD138+ CD38+), between SLE and HD BM. For both SLE and HD, CD138+ PC are at a higher frequency in BM than PBL. Expression of Ki-67 associates with the PBL compartment where it is found on all PC subsets regardless of CD19 or CD138 expression. Transcriptomic analysis identifies an interferon (IFN) gene signature in transitional B cells in the SLE BM, but surprisingly also in the BM PC derived from SLE. BM PC and B cells phosphorylate STAT1 in response to type I IFN stimulation in vitro , but with decreased fold change compared to those from the PBL. While BM PC bind type I IFN receptor-blocking antibody anifrolumab, it is to a lesser degree than circulating B cells. Anti-nuclear autoantibodies (ANA) are found in the BM supernatant and PBL serum of SLE patients. Both SLE and HD BM-derived PC have increased survival compared to their PBL counterparts when treated with verdinexor. In summary, these findings show evidence of IFN activation in BM PC from SLE.

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40–CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.

Background Early initiation of effective treatment is associated with positive long-term prognosis for patients with rheumatoid arthritis (RA). Currently, there are no biomarkers in clinical use to predict treatment response. A predictor of treatment response may be the B-cell compartment, as this is altered in RA patients, making it a potential candidate for predicting treatment response. In this study, we sought to identify B-cell subset(s) at diagnosis that might be associated with Clinical Disease Activity Index (CDAI) remission at 24-week follow-up. Methods Seventy early RA patients from the NORD-STAR trial, recruited from two Swedish sites, and 28 matched healthy controls, were included in this spin-off study. In NORD-STAR, all patients were randomized to methotrexate (MTX) combined with 1) prednisolone, 2) anti-TNF (certolizumab-pegol), 3) CTLA4-Ig (abatacept), or 4) anti-IL-6R (tocilizumab). Circulating B-cell subsets at diagnosis were assessed by flow cytometry. The primary outcome measure was remission according to CDAI ≤ 2.8. A multivariate two-part discriminant analysis was performed to assess whether B-cell subpopulations at diagnosis could predict remission at 24 weeks. Subsequent univariable statistical analyses were performed using t-tests, Mann-Whitney U, or Kruskal-Wallis tests, as appropriate. Correlations were analyzed using Spearman or Pearson tests, depending on data type. The impact of specific B-cell populations on remission at week 24 was assessed using logistic regression models. The logistic regression model was also used to simultaneously visualize the sensitivity and specificity of the model for all possible values of the exposure (B-cell subpopulations) in predicting the outcome. Results Patients who achieved CDAI remission at 24 weeks had higher proportions of transitional ( p  < 0.01) and CD21 − PD-1 + ( p  < 0.01) B cells at diagnosis compared to those who did not. When the two B-cell populations were combined, the sensitivity and specificity for remission, including all treatment arms, were 59% and 86%, respectively. Stratification of the patients by treatment arm revealed a significant negative correlation between the proportion of transitional B cells at baseline and disease activity after 24 weeks of treatment with either MTX and prednisolone or anti-IL-6R. Conclusions Our results indicate that transitional and CD21 − PD-1 + B cells are associated with remission in early RA. Clinical trial number Not applicable.

▪ Abstract  Our views regarding the origins and functions of splenic marginal zone B cells have changed considerably over the past few years. Perspectives regarding the development and function of these cells vary considerably between investigators studying human and rodent immunology. Marginal zone B cells are now recognized to constitute a distinct naive B lymphoid lineage. Considerable progress has been made regarding the mechanisms involved in marginal zone B cell development in the mouse. Many of the molecular events that participate in the retention of this lineage of B cells in the marginal zone have been identified. Here, we discuss the functions of these cells in both innate and adaptive immunity. We also attempt to reconcile differing viewpoints regarding the generation and function of marginal zone B cells in rodents and primates.

A hallmark of systemic lupus erythematosus (SLE) is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies; however, the antibody-independent features of the B-cell compartment in SLE are less understood. In this study, we performed an extensive examination of B-cell subsets and their proinflammatory properties in a Chinese cohort of new-onset SLE patients. We observed that SLE patients exhibited an increased frequency of transitional B cells compared with healthy donors and rheumatoid arthritis patients. Plasma from SLE patients potently promoted the survival of transitional B cells in a type I IFN-dependent manner, which can be recapitulated by direct IFN-α treatment. Furthermore, the effect of IFN-α on enhanced survival of transitional B cells was associated with NF-κB pathway activation and reduced expression of the pro-apoptotic molecule Bax. Transitional B cells from SLE patients harbored a higher capacity to produce proinflammatory cytokine IL-6, which was also linked to the overactivated type I IFN pathway. In addition, the frequency of IL-6-producing transitional B cells was positively correlated with disease activity in SLE patients, and these cells were significantly reduced after short-term standard therapies. Thus, the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients, which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.